Aqueous pharmaceutical compositions in the form of eye drops, nasal drops or other, which comprise sodium cromoglicate [disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane] having antiallergic activity as an active ingredient, have been used for preventive and therapeutic treatment of allergic conjunctivitis and allergic rhinitis.
It has been known that turbidity or precipitation tends to quite frequently appear in an aqueous pharmaceutical compositions comprising sodium cromoglicate as an active ingredient (see, for example, Japanese Patent Publication (KOKOKU) Nos. (Hei)4-66452/1992 and (Hei)4-78613/1992). It is recognized that the turbidity or precipitation is formed because a quaternary ammonium compound such as benzalkonium chloride, which is added as a preservative, reacts with sodium cromoglicate in the presence of trace metal ions (Pb.sup.2+, Ca.sup.2+, Cu.sup.2+, Al.sup.2+, Fe.sup.2+, Fe.sup.3+, Zn.sup.2+, Mg.sup.2+ or other) contained in the aqueous solution. Recent researches by the inventors of the present invention revealed that the reaction of benzalkonium chloride and sodium cromoglicate as well as resulting precipitation of reaction products are remarkably accelerated especially when concentrations of calcium ion and magnesium ion in the aqueous solution exceed 1 ppm and 10 ppm, respectively.
The generation of turbidity or precipitation seriously disturbs a process of manufacturing an aqueous pharmaceutical composition comprising sodium cromoglicate as an active ingredient, and this is also a significant problem from a viewpoint of storage stability of pharmaceutical preparations. However, considerable amounts of magnesium and calcium are contained as unavoidable impurities in bulk powder of sodium cromoglicate used as a raw material of pharmaceutical preparations, and distilled water for injection used as a solvent also contains a trace amount of metal ions. Therefore, it is practically impossible to achieve complete prevention of the generation of turbidity or precipitation by improving quality of raw materials and circumstantial conditions of a manufacturing process.
For the manufacture of an aqueous composition comprising sodium cromoglicate, methods of adding a precipitation inhibitor (sequestering agent) such as a chelating agent or a nonionic surfactant to the aqueous composition have thus been proposed as means to effectively prevent the generation of turbidity and precipitation.
For example, the following means have been proposed: an aqueous composition comprising sodium cromoglicate as an active ingredient that is added with an effective amount of a pharmaceutically acceptable chelating agent or sequestering agent when a concentration of a metal ion in the aqueous solution exceeds 0.40 ppm (Japanese Patent Publication (KOKOKU) No. (Sho)54-25082/1979); a water-soluble pharmaceutical preparation added with benzalkonium chloride as a preservative and polyoxyethylene sorbitan monooleate or polyoxyethylene hardened castor oil as an agent for preventing turbidity or precipitation (Japanese Patent Publication (KOKOKU) No. (Hei)4-66452/1992); and an external pharmaceutical preparation containing benzalkonium chloride as a preservative and a nonionic surfactant such as polyoxyethylene hardened castor oil in respective particular amounts (Japanese Patent Publication (KOKOKU) No. (Hei)4-78613/1992).